Project Summary/Abstract Adverse childhood experiences (ACEs), such as abuse and neglect, have been strongly and consistently linked to increased risk for a variety of psychiatric diseases, including anxiety disorders, mood disorders, and substance abuse disorders. These diseases extract a massive emotional and economic toll on society, and their combination can be devastating and even deadly in cases of suicide and overdose. The increased risk for psychiatric disease following ACEs can persist for decades, well into adulthood, and combine with adult stressors to provoke the onset of symptoms. Despite the huge burden of psychiatric disease on our nation, and the clear impact of ACEs in producing that burden, we still have little understanding of the underlying neural circuits mediating increased psychiatric risk following adverse childhood experience. Why does stress during a window of early life confer elevated psychiatric disease risk? And why are some individuals nevertheless resilient? I hypothesize that stress during an early-life period of ongoing development in the midbrain dopamine system may alter the structure, and therefore function, of neuromodulation in the adult brain, dysregulating adult stress responses. Furthermore, I propose that individual variation in the dopamine circuit alterations produced by early life stress may explain individual variation in the later development of disease symptoms. This project will elucidate the neural circuit basis of susceptibility to psychiatric disease using mice as a model system. Mice of both sexes will be exposed to varying positive and negative early life conditions, and then tested for susceptibility or resilience to stress in adulthood using a panel of behavioral tests measuring affective function and motivation. Using cutting edge neural circuit imaging techniques, including CLARITY, optogenetics, and fiber photometry, I will ask whether the strength of specific brain connections in each individual subject is predictive of that subject?s susceptibility or resilience to stress. My CLARITY approach will allow me to search broadly and systematically for connections within the dopamine circuitry that are relevant to stress susceptibility, while my optogenetics and fiber photometry approach will allow me to track specific connection strengths in awake behaving animals before, during, and after the onset of behavioral changes. This project represents my vision of harnessing individual variation in behavior to gain insight into core circuit dysfunctions underlying polygenic and heterogeneously presenting psychiatric disorders. Together, the results from these studies will lead to understanding how the dopamine system regulates complex behaviors and will guide translational work to create sophisticated new circuit therapeutics for some of the most difficult problems in psychiatric medicine.